The ultimate goal of this project is to gain insight into polyglutamine-induced neurodegeneration by identifying genes, pathways and molecular mechanisms involved in the pathogenesis of spinocerebellar ataxia type 1 (SCA1). A Drosophila model of SCA1 was created by generating flies that express either normal or expanded human SCA1 transgenes. This fly model recapitulates the cellular phenotypes observed in SCA1 patients including the formation of nuclear inclusions (NI) and progressive neuronal degeneration. Capitalizing on the power of Drosophila genetics, two large genetic screens were designed to identify genes that modify a SCA1 neurodegenerative phenotype in the eye. The first screen yielded modifiers of the SCA1 phenotype when gene activity was decreased; the second screen yielded SCA1 modifiers when gene activity was increased. Both suppressors and enhancers of the neurodegenerative phenotype were obtained from each screen. The first aim of the proposed work is to identify the genes that modify the SCA1 neurodegenerative phenotype. These modifiers will be further characterized in sensitive viability and locomoter assays that allow the quantification of their modifier effects. The most powerful suppressors will be selected for further studies. To investigate whether different polyglutamine disease share common mechanisms of pathogenesis, the SCA1 modifiers will be tested in fly models of Huntington disease and polyglutamine toxicity. Finally, because the normal function of the SCA1 gene may be relevant to pathogenesis, the function of the Drosophila SCA1 gene will be investigated by generating lack-of-function mutations and transgenes for its over expression. In future studies, the most promising SCA1 suppressors characterized in flies will be investigated in the SCA1 mouse model, and in mouse models of polyglutamine disease. These genes may also be relevant to research aimed at treating other neurodegenerative proteinopathies such as Alzheimer disease and Parkinson disease. They will provide valuable targets for future pharmacological research aimed at developing drugs for therapy.